GOOD AFTERNOON. WELCOME TO WEDNESDAY AFTERNOON LECTURE SERIES. WE'RE PARTICULARLY PLEASED TO HAVE DR. PETER AGRE DR. AGRE WON THE 2003 NOBLE PRIZE IN CHEMISTRY, COVERING THE FAMILY OF WATER CHANNEL, PROTEINS FOUND THROUGHOUT NATURE UNDERLYING NUMEROUS PROCESSES AND CLINICAL DISORDERS. AND THIS GOES BACK TO THE LATE 80s. WHEN I DID MY POST-DOC IN SAN DIEGO, THE DEPARTMENT OF BIOLOGY AS AN MD. IT WAS A TOUGH TIME. AND I UNDERSTAND THIS THE Ph.D.s LOOKED A LITTLE BIT DOWN TO US ON THE MD SIDE. BUT AT ANY RATE, IN THIS DEPARTMENT OF BIOLOGY, SEVERAL LABORATORIES IN SAN DIEGO, WORKED ALREADY ON THE WATER CHANNELS. IT WAS A MOMENTOUS DISCOVERY. IT CAME ABOUT SERON DIPLY STUDIOING RH, THE BLOOD SYSTEM AND CONSTANTMENT. THAT TURNED OUT TO BE ANOTHER SYSTEM AND THIS WAS THE [INAUDIBLE] HEAR. HERE. LATER, HE BECAME DEEPLY INVOLVED IN MULTIPLE GLOBAL ISSUES AS APPROPRIATE WITH THIS TRACK RECORD. HE CURRENTLY DIRECTS THE JOHNS HOPKINS MALARIA RESEARCH INSTITUTE, LEADING FIELD RESEARCH IN [INDISCERNIBLE]. AS CHAIR OF THE HUMAN RIGHTS OF ACADEMICS, HE LED SCIENCE SCIENTISTS, ENGINEERS AND HEALTH PROFESSIONALS WORLDWIDE. [INDISCERNIBLE] FOR THE ADVANCEMENT OF SCIENCES. MEETINGS WITH LEADERS OF KINS INCLUDING CUBA, THE DEMOCRATIC REPUBLIC -- PEOPLES REPUBLIC OF KOREA, SO THAT'S NORTH KOREA. MYANMAR, AND IRAN. WE'RE REALLY PLEASED TO HAVE YOU HERE, LOOKING FORWARD TO YOUR PRESENTATION. I CAN'T TELL YOU EXCITED I AM, [INDISCERNIBLE] AND YOU GOT THE BETTER END OF THE RH RESEARCH. [APPLAUSE] >> GOOD AFTERNOON. [INAUDIBLE] >> CHANGES IN GLOBAL WATER STATUS [INAUDIBLE] MELTING THE POLAR ICE CAPS. [INAUDIBLE] IN BIOLOGY WATER IS ALWAYS IMPORTANT. AND IT'S SOMETHING–r I REALLY DIDN'T PAY MUCH ATTENTION TO WHEN I WAS A STUDENT. TAKING PHYSIOLOGY COURSES. WITH THE NOTION THAT SALT HAS SPECIFIC TRANSPORTER, BUT WATER WENT WHERE IT NEEDED TO GO. TURNS OUT SPECIAL PLUMPING SYSTEM FOR WATER. THAT'S WHAT I'M TALKING ABOUT, THE AQUA POREN. SO THE BACKGROUND IS REPRESENTED IN THIS SLIDE M OF. ON THE LEFT YOU'D SEE A SIMPLE MEMBRANE VIOLATER, PERMEATED BY SIMPLE DIFFUSION OF WATER MOLECULES. BACK AND FORTH ACROSS THE MEMBRANES. BUT IT'S CLEAR THAT THERE IS SOMETHING TISSUE, SOME [INAUDIBLE]. THESE ARE RECOGNIZED TO HAVE THE NEEDS FOR SPECIAL WATER SELECTED CHANNELS, [INAUDIBLE] IN RED CELLS.q SO THIS PROCESS OF OSMOSIS OCCURS IN SOME TISSUES RAPIDLY. RAPID OSMOSIS. NOW, IN 1970, ROBERT MACY AT THE UNIVERSITY OF BERKELEY, A PHYSIOLOGIST, DECIDED THE RESERVOIR AND DISCOVERED THAT FLUID STOPPED WATER TRANSPORT IN RED CELLS. HE COULD RESTORE IT, TURN IT OFF AND ON. AND HE PREDICTED THERE MUST BE WATER SELECTIVE CHANNELS, NEITHER HE OR OTHER INVESTIGATORS WERE ABLE TO IDENTIFY IT, FOR A VARIETY OF TECHNICAL REASONS. SO THE OBSERVATION OF THE FIRST WATER CHANNEL WHICH WE NOW CALL AQUA POREN ONE WAS A SHEER SERENDIPITOUS OBSERVATION. AS HE SAID, MY INITIAL WORK AS A HEMATOLOGIST, VERY SMALL LAB IN JOHNS HOPKINS, WAS ON THE BIOCHEMICAL NATURE OF THE RHESUS BLOOD GROUP ANTIGEN. IN 1982 SEVERAL INDEPENDENTLY DEMONSTRATED THEY COULD SURFACE LABEL RED CELLS FROM RHD POSITIVE INDIVIDUALS AND LIABLE A 32 KILADALTON BAND, DID NOT LABEL NEGATIVE RED CELLS. NOW, WHAT WE SAW IN THE INITIAL SODIUM [INDISCERNIBLE] GEL SHOWN HERE, THIS IS STAINED BY SILVER, I SHOULD SAY. A CLEAR 32 KILDALTON BAND. SMALLER BANDS IN EACH SPEAKERIES, WHICH WE -- SPECIES, WHICH WE DESMESSED AND DEGRIDIDATION. NOTHING WAS SUSTAINED, YOU COULDN'T SEE. SO WE WERE HOT IN PURSUIT OF THE RHESUS BLOOD GROUP BUT THE SECOND PROTEIN FELL IN OUR LAPS. WE SOONER OR LATER FIGURED THAT THE SECOND PROTEIN WAS NOT A BREAK DOWN PRODUCT, BUT A CONTAMINANT. WHAT A LOWLY START FOR A SCIENTIFIC PROJECT, A CONTAINMENT. BUT IT WAS VERY ABUNDANT, HAD INTERESTING END TERMINAL DEGRADATION SEQUENCE. WE DECIDED WE WOULD CLOP IT OUT. IF WE GOT THE cDNA, THAT WOULD SHOW HOME LOGS, THEN WE WOULD KNOW WHAT IT DID. AND THE NEW SEQUENCE SHOWED A 67 VIOLATER SPANNING MEM BRAIN -- 6 VIOLATER SPANNING MEMBRANE PROTEIN WITH AN INTERNAL REPEAT. [INDISCERNIBLE] INVERTED WITH RESPECT TO EACH OTHER. AND THE GENETICS DATABASE HAD SEVERAL HOLM LOGS, NONE FUNCTIONALLY DEFINED. PROTEINS FROM THE LENS OF EYE, PROTEINS FROM THE BRAINS OF INSECTS. PRONE THAT ALLOWED BACTERIA TO USE GLYCEROL AS CARBON FILL ERS. GENE FRAGMENTS FROM PLANT TISSUES. SO WE WERE STUCK. WE DIDN'T KNOW THE FUNCTION OF THIS NEW PROTTEEN. I THINK YOU'RE AWARE THAT PROTEIN WOULD IT A FUNCTION IS A SCIENTIST WITHOUT A GRANT. [LAUGHTER] WITHOUT A GRANT, IT GETS BAD. THERE IS GREAT IMPETUS TO FIGURE OUT THINGS IN SCIENCE. BUT I TALKED TO ALL MY COLLEAGUES AND THEY HAD INTERESTING SUGGESTIONS. IT DIDN'T QUITE FIT TOGETHER. SO WE DID WHAT ANY FAMILY WOULD TO. WENT ON VACATION. NOW, AS SCIENTISTS, WE LOVE OUR WORK. EVERY YEAR WE WENT TO NATIONAL PARKS CAMPING. MY WIFE SAID LET'S ASK THE KIDS WHICH NATIONAL PARKS THEY WANT TO GO TO NEXT YEAR? WE HAD BEEN TO YELLOW STONE, AND OTHERS. WE ASKED THE KIDS, THEY SAID DISNEY WORLD, WHICH IS NOT A NATIONAL PARK. HERE ARE THE LITTLE DARLINGS. SO WE TOOK THEM UP AND WE WENT TO THE EVERGLADES. AND THEN WE WENT TO DISNEY WORLD. ON THE WAY WACK TO BALTIMORE, WE STOPPED IN CHAPEL HILL, NORTH CAROLINA WHERE I HAD SPENT 3 YEARS AS A POSTDOCTORAL FELLOW. THIS IS A WONDERFUL TIME, FRANCIS COLLINS IS A MEDICAL RESIDENT AT THE HOSPITAL. WAS A REALLY HIGH. WE BECAME GOOD FRIENDS WITH JOHN PARKER, A HEMATOLOGIST. I STOPPED TO SEE JOHN. WE'RE DRIVING BACK TO BALTIMORE. TOLD-OF HIS NEW PROTEIN. I WAS CONVINCED WOULD BE INTERESTING, COULDN'T FIGURE OUT WHAT IT COULD BE DOING. I ASKED HYMN IF IT MIGHT BY -- HIM IF IT MIGHT„i BE AN OXYGEN CHANNEL. JOHN LOOKED AT ME, SAID I THINK THE SALT WATER CHANNEL, SOMETHING PHYSIOLOGISTS HAVE BEEN SEARCHING FOR, FOR CENTURIES, THE CREDIT GOES TO JOHN. WE PURSUED THIS, WE COLLABORATED WITH JOHN HOPKINS AND EXPRESSED NEW COMPLEMENTARY RNA IN FROG EGGS. THEY HAVE A VERY LOW INHERENT WATER PERMEABILITY. ABOUT A MILLIMETER IN DIAMETER. IDEAL EXPRESSION SYSTEM. WHEN TRANSFERRED TO DISTILLED WATER, IMMEDIATE APPARENT DIFFERENCE. THE TEST SITE EXPLODED PRODUCING MUCH JUBILATION IN THE LABORATORY. [LAUGHTER] THIS IS GREGORY PRESTON, THE POST-DOC THAT DID THE FIRST DISEASED. I TOOK THE SNAPSHOT OF GREG 3 YEARS AFTER THE REPORT. HE WAS STILL CELEBRATING. THE DISCOVERY IS THE AWARD IN SCIENCE. WE DIDN'T REALLY KNOW SO ISSUE WHAT WE WERE GETTING INTO. [TECHNICAL DIFFICULTIES]. SINGLE CHANNEL. TOP TO BOTTOM. ALLOWING WATER TO MOVE FROM AN EXEDRA CELLULAR VESTIBULE TO AN INTRACELLULAR VESTIBULE. WATER IS AN INTERESTING CHEMICAL. MOLECULE. IT DOESN'T EXIST AS AN ISOLATED H2O IT EXISTS IN A SEVERE STORM. IN A CONSORTIUM. HYDROGEN BINDING. IN THE CHANNEL, THE STRUCTURE SHOWING THIS HERE ALLOWS TRANSPORT OF WATER IN SINGLE FILE WITH BARRIERS TO THE MOVEMENT OF THE CHARGED ION, AND HYDROGEN BONDING, THE VERY CENTER OF POINTED -- THESE 2 REPEATS THAT I MENTIONED BRIEFLY. THIS WATER MOLECULE IS ISOLATED FOR A BILIANTH OF A SECOND, ENOUGH TO PREVENT PASSAGE OF PROTONS. IT'S VERY EFFICIENT. THIS IS WORK OF DAVID [INDISCERNIBLE] MULTIPLE LABORATORIES GOT ACTIVE, AND TOGETHER, SERIES OF 13 HIM HOMLOGS HAVE BEEN CLONED OUT. HUNDREDS FROM OTHER SPECIES. BASICALLY EVERY LIVING ORGANISM HAS WITHIN OR MORE AQUA POREN. TWO BASIC FORMS. HIGHLIGHTED THE BLUE. WE CALL THOSE [INDISCERNIBLE]. AND I'LL TELL YOU ABOUT EACH OF SEVERAL OF THESE. AQUAPORIN, WHERE DOES IT EXIST IN THE KIDNEY? WE KNEW IN THE RENAL TUBULES, BY NOT VERY SOPHISTICATED. WE HAD THE GOOD FORTUNATE DO [INDISCERNIBLE] NIELSON, A FOG I RESPECT AFELLOW HERE AT THE HEART LUNG AND BLOOD INSTITUTE WORKING ON RENAL MECHANISMS. TOGETHER WE WORK FORWARD A DECADE ON VARIETY OF PROJECTS. THE FIRST BEING THE LOCATIONS OF THE AQUAPORIN ONE MOLECULE IN THE KIDNEY. YOU CAN SEE THE NEPHRON UNIT ON THE LEFT SIDE OF THE DIAGRAM, HIGHLIGHTED. AFTER PASS THROWING THE [INDISCERNIBLE] PHIL TRAITS THROUGH THE -- FILTRATES. IT'S HIGHLIGHTED IN GREEN. THAT'S WHERE WATER PERMEABILITY IS HIGH. THIS IS OUR LOGARITHMIC COMPILATION IN THE RIGHT. SO HIGH WATER PERMEABILITY. THEN THE [INDISCERNIBLE] THEY LEGIBLE EMPTYING INTO THE COLLECTING DUCT WHERE THE WATER IS REGULATED PERMEABILITY. SO THE AQUAPORIN WITHIN PROTEIN WAS [INDISCERNIBLE]. IN THE BRUSH QUARTER, LATERAL -- BASE OF THE LATERAL, YOU CAN SEE THE GOLD DOT FROM THE BEAUTIFUL LABELING. INTENSE PRESENCE OF THIS PROTEIN IN THE SURFACE. SO IT EXPLAINS HOW WATER TRANSCELLULAR FASHION THROUGH THE NEPHRON. GOING FROM THE PRIMARY URINE TO THE APICAL SURFACE THROUGH THE BASE OF THE LATERAL MEMBRANE, FOLLOWING THE RADIANT CREATED BY SALT AND SUGAR TRANSPORTERS. NOTICE THE TIGHT JUNCTIONS PREVENT MOVEMENT OF WATER FROM BETWEEN THE CELLS. SO BEING A MEDICAL DOCTOR, WE WERE VERY CURIOUS, WHAT IS THE CLINICAL SIGNIFICANCE OF THIS PROTEIN? AND WE IMAGINED THEY COULD BE CATASTROPHIC. WERE WRONG. THIS IS WHERE THE BLOOD GROUP ANTIGEN CAME VERY INTERESTING, BECAUSE AS TRANSFUSION MEDICINE SPECIALISTS, NONE OF YOU WILL BE SURPRISED TO THINK A RED CELL MEMBRANE PROTEIN COULD BE AN ANTIGEN. YOU WOULD ASSUME SO. OUTSIDE OF THE FIELD THAT'S NOT TOO WELL UNDERSTOOD. BY WHEN WE DID CHROMOSOMAL LOCALIZATION OF THE GENE LOCUST, THIS IS BEFORE FRANCIS AND THE [INDISCERNIBLE], FLUORESCENCE HYBRID STATION. TURNED OUT THE GENE LIT UP IN THE SHORT ARM OF HUMAN CHROMOSOME 7. NOW, THE COMPILATION IN THE ATLAS DIDN'T SAYING ANYTHING ABOUT BLOOD GROUP ANTIGENS BUT I HAPPENED TO NOTICE WHEN I WAS VISITING THE NEW YORK BLOOD CENTER, MY FRIEND REDMAN, THERE WAS A HUMAN CHROMOSOME 7 ON HIS WALL WITH THE LONGER ARM, AN AREE FROMO POINTING. SHORT ARM, AN ARROW. CO. THAT'S VERY INTERESTING! WHAT IS THAT CO ON THE SHORT ARM? THAT'S THE COLTEN BLOOD GROUP ANTIGEN. HE STARTED TO EXPLAIN, PROTEASE RESISTANT ANTIGEN. NO ONE KNEW WHAT IT WAS. THAT WAS A VERY IMPORTANT CONVERSATION I HAD WITH BEHIND THE WHEEL. I WOULD LIKE TO PROPOSE WE RENAME COLTEN THE KOLVIN ANTIGEN. BASED ON THAT WE DISCUSSED DAVID AND HIS TEAM IN BRISTOL, THE INTERNATIONAL BLOOD GROUP REFERENCING SYSTEM A WONDERFUL COLLABORATIVE ORGANIZATION. AND WE WERE ABLE TO OBTAIN BLOOD, IRON, F URINE, DNA, FROM A VARIETY OF INDIVIDUALS. WE CONFIRMED THAT THE COLTTEN POLLY MORPHISM WAS A SIMPLE SIBSTITUTION AT THE 45th RESIDUE, EXTRA CELLULAR LOCATION. THAT IS ANNOT TOO IMPORTANT. ALMOST EVERYBODY IS COLTEN A OR AB. BUT IN THE WHOLE WORLD AT THE TIME, ONLY HALF A DOZEN COLTEN NULL INDIVIDUALS HAVE BEEN KNOWN. IT BECAME IMMEDIATELY INTERESTING TO US, AND THROUGH OUR COLLEAGUES AT THE INTERNATIONAL BLOOD GROUP REFERENCING SYSTEM WE WERE ABLE TO TRACK DOWN 3 DIFFERENT INDIVIDUALS. GET THEM TO COME TO JOHNS HOPKINS FOR CLINICAL PHENOTYPING. IT'S AMAZING THE PAIR THAT SCIENCE HAS WHEN PEOPLE WORK AS COLLEAGUES. SO SHOWN HERE WITH PERMISSION IS A COLTEN NULL INDIVIDUAL SHOWN IN THE CENTER. RETIRED SCHOOL TEACHER FROM THE SOUTH OF FRANCE. AND ALONG SIDE HER IS A FRENCH SPEAKING POST-DOC. AND LANDON KING, A POST-DOC IN THE LAB THAT DID A NUMBER OF PHENOTYPIC STUDIES. BASICALLY, EVERYTHING HE TESTED IN THE KIDNEY TURNED OUT NORMAL. WE WERE CONVINCED THERE WAS GOING TO BE A CLINICAL PHENOTYPE. BUT NOTHING TURNED¨— OUT UNTIL HE DID A SIMPLE OVERNIGHT THURSDAYING. WE GO TO BED AND SLEEP 7 OR 8 HOURS WE DRINKING NO WATER. IN THE MORNING WE EMPTY OUR BLADDER. AND THE LAST FEW DROPS OFF URINE ARE HIGHLY CONCENTRATED. SO IN THE MORNING, WHEN WE AWAKE P, OUR YOU'RE N TENNISTY WILL BE ATHOUSAND. [INDISCERNIBLE] ALL HOMOZYGOUS. THEY'RE STUCK AT ABOUT 400. THEY CAN'T CONCENTRATE ANY FURTHER. IN TERMS OF NORMAL LIFE WITH REACTIVE TO FLUIDS AND AIR CONDITIONING THEY DO FINE. IF THEY WERE THIRSTED LONGER, THEY WOULD CLEARLY GET IN TROUBLE. A DISTINCT FORM OF DIABETES ENCRYPTTIS. NOW, LANDON IS A PULMONARY SPECIAL ES. LOOKED AT AKWAN POREN DISTRIBUTION -- PULMONARY MICROVASCULARTURE. THIS IS A NICE GRAPHIC OF A HUMAN CAPILLARY. THERE IS INTENSE LABELING OF THE SURFACE. CAPILLARIES ARE PERMEATED BY WATER. AND IN THE SECOND PHENOTYPING HE EVALUATED PULMONARY CAPILLARY, WATER TRANSPORT. HE DID THIS AT JOHNS HOPKINS USING A HIGH RESOLUTION CT SCAN OF THE LUNG, A YOUNG SCIENTIST WHO HAD COME FROM ALGERIA. I THINK YOU KNOW HIM. HE WORKED HERE FOR A WHILE. USING HIS TECHNIQUE, WE EVALUATED WATER TRANSPORT IN THE LUNG. THESE ARE IMAGES FROM NORMAL. WHAT I'D LIKE YOU TO SEE IS AT BASELINE, A THIN LINE AIR SPACE, AND AFTER INFUSION OF 3-LITERS OF PHYSIOLOGICAL SALINE, WHAT I'D LIKE YOU TO SEE, THE SCREENIALS HAVE BECOME EXPANDED. THIS IS TRUE FOR [INDISCERNIBLE]. BUT THE RELEASE OF FLUID FROM THE VENIALS TO THE PERIBRONCHIAL SPACE WHICH LOOKS LIKE THIS, FROM HERE TO HERE, DOES NOT OCCUR FROM THE NULL INDIVIDUALS. THERE IS A BARRIER TO THE ENTRY AND RELEASE OF WATER FROM THE VASCULAR SPACE. NOW, WE DON'T KNOW THE PROCEED FOUND CLINICAL CONSEQUENCES OF THIS. BUT ADVERSE, THE LONG TERM FROM THE SECRETARY ORGANIZE TO KNOW OBSORBIVE. THIS MAY BE ONE OF THE REASONS. WE'RE NOT SURE ABOUT THAT. SO A LOT OF INTEREST WAS EXPRESSED BY PHYSIOLOGISTS AROUND THE WORLD. ACTUALLY, SOMETIMES THERE IS SO MUCH INTEREST, I FELT A LITTLE OVERWHELMED. IT WAS MARK NEPER THAT WAS ON IT RIGHT AWAY. WE -- VERY PLEASED THAT WE GOT THE NEW WATER CHANNEL FROM THE NEPHRON. BUT THE COLLECTING DUCT, IMPORTANT PART OF THE KIDNEY. THIS IS WHERE BASSO PRESSANTS SECRETE CAUSING WATER ABSORPTION TO BE INCREASED. SECOND MEMBER OF THE FAMILY WAS CLONED, REFERRED TO AS AQUAPORIN 2, IN THE COLLECTING DUCT. AND INTERESTING DISTRIBUTION IN COLLECTING DUCT. IT'S AN INTRACELLULAR VESICLE, AND AFTER INFUSION OF PHYSIOLOGICAL LEVELS OF VASO PRESSANT -- THIS IS A CLASSICAL PAPER. FOR THE COLLEAGUES PUBLISHED HERE TEN YEARS AGO. HARD TO IMAGINE, TEN YEARS ALREADY, MARK. EXCUSE ME. 20. THANKS. [LAUGHTER] WHEN YOU GET TO BE MY AGE, THE NUMBERS GET HARD. 20 YEARS! THAT MEANS WE'RE 66. SO THE AQUAPORIN MOVED TO THE SURFACE, WATER CAN ENTER. NOW, CLINICALLY, THIS IS REALLY IMPORTANT. INHERITED DEFECTS IN THE AQUAPORIN 2 GENE CAUSES SEVERE FORM OF DIABETES ENCRYPTIS. THIS IS WORK PUBLISHED BY PETER DEAN AND PAUL IN THE NETHERLANDS. FORTUNATELY, IT'S VERY RARE. BUT ACQUIRED DEFECTS ARE VERY COMMON. WITH OVER EXPRESSION BEING DOWNED IN SITUATIONS SUCH AS CONGESTIVE HEART FAILURE. LEADING TO MASSIVE FLUID–r RETENTION. AND UNDER-EXPRESSION, OF COURSE, POLY YOU ARIA. BED WETTING. SO IT'S A VERY IMPORTANT MOLECULE. I'M GOING TO SKIP THROUGH THE FAMILY AND TELL YOU A LITTLE BIT ABOUT EACH OF THE OTHER MEMBERS OF THE GENE FAMILY, WHO DID THE WORK. AQUAPORIN 0 KNOWN AS MIT IS PRESENT IN THE LENS. THE SOURCE OF -- IT CAUSES CATARACTS IN SMALL CHILDREN. MUTATIONS IN THE GENE. THIS IS 2 DIFFERENT FAMILIES PERREPORTED BY OUR COLLEAGUES FROM LONDON. AND YOU CAN'T SEE ANYTHING FROM THE VISUAL EXAMS, THE CATARACT HAS MULTIPLE OPACITIES IN THIS MUTANT FAMILY. AND A SINGLE CENTRAL OPACITY IN THIS FAMILY. SO LOSS OF VISION, INTELLIGENCE. AND IT'S BELIEVEED THAT DESTABILIZING MUTATIONS WILL PROBABLY BE THE PREDISPOSING FACTORS FOR THE RECURRENCE OF CATARACTS IN OLDER INDIVIDUALS. ANOTHER, AQUAPORIN 4, IN THE BRAIN. IN THE PERIVASCULAR [INDISCERNIBLE]. CAPILLARIES IN THE BRAIN ARE, OF COURSE, SURROUNDED BY A PARASITE WITH A BASE MEMBRANE AND THE [INDISCERNIBLE], THESE SUCTION CUPS ARE PROVIDED SUPPORT AND BARRIER TO MOVING THE FLUID FROM THE BRAIN -- FROM VASCULAR SPACE TO BRAIN [INDISCERNIBLE]. THIS IS EXACTLY WHERE AQUAPORIN 4 -- THIS BEAUTIFUL . AT THE PERIVASCULAR MEMBRANE. NOT AT THE OTHER MEMBRANE. VERY SPECIAL LOCATION. NOW, THIS LOCATIONS, OF COURSE, IS BLOOD BRAIN BARRIER. IT PREDICTED THAT DEFECTS IN THE -- CAUSING THE BRAIN EDEMA WOULD INVOLVE THE PATHWAYS WITH AQUAPORIN 4. AND THAT WAS FIRST CONFIRMED BY OUR COLLEAGUES IN A GROUP LED BY [INDISCERNIBLE], YOUNG IRANIAN SCIENTIST WORKING IN A HOSPITAL WHO LOOKED AT 2 DIFFERENT MOIST GROUPS, NORMAL MICE, AFTER DEFINING BRAIN INJURIES, SUSTAINED INFARCT AND EDEMA. THE MUTANT MICE ARE DEFECTS IN BRACKETING MOLECULE. THE AQUAPORIN 4 IS NORMAL, BUT IT'S PRESENT ALONG LOCATIONS. THE ALPHA [INDISCERNIBLE]. THESE MICE HAVE MUCH LESS EDEMA AND INFARCT. THIS IS INDEPENDENTLY REPORTED AS OTHER MOUSE MODELS, GROUPS IN SAN FRANCISCO, AND HUNGRY, AND IT'S CLEAR THAT IN ADDITION OF THE AQUAPORIN 4 MOLECULE, IN TERMS OF PRIMARY MARIE FUNCTION OR LOCATION, WOULD BE OF BENEFIT FOR INDIVIDUALS DEVELOPING BRINE EDEMA. AND BRAIN EDDIMA IS A TRAGIC, VERY COMMON PROBLEM. STROKE IS THE THIRD LEADING CAUSE OF DEATH IN THE INSTRUCTION. MANY CASES, THE INDIVIDUAL WITH A STROKE SUCCUMBS NOT 250 THE INDARK BUT TO THE BRAIN EDEMA. THIS IS A BIG PROBLEM WITH MANAGEMENT OF BRAIN TUMORS. THIS IS AN MRI FROM 65-YEAR OLD LADY WHO HAD A LARGE [INDISCERNIBLE]. YOU CAN SEE THAT AROUND IT, WAS MASSIVE AMOUNT OF BRAIN EDEMA. SURGICALLY IT WAS REMOVED. THIS IS THE NEXT DAY. THE BRAIN EDEMA PERSISTED. IT TOOK MONTHS FOR THAT TO RESOLVE. THIS IS A BIG PROBLEM. THIS IS THE PROBLEM I KNOW WELL. THIS IS MY WIFE, MARY, LAST YEAR. SHE HAD A COMPLETE RECOVERY. DOING JUST FINExD NOW. BUT THE MANAGEMENT OF BRAIN EDEMA EFFECTS PEOPLE ALL AROUND YOU. IT'S A BIG PROBLEM. ANOTHER MEMBER OF THE FAMILY, AQUAPORIN 5, IS¨— PRESENT IN„i SECRETARY GLANDS. MOLECULAR, CELLULAR, SWEAT GLANDS, THE LAST MEMBRANE WATER CROSSES DURING THE GENERATION OF SWEAT, SALT AND SALIVA. NOW, VERY SIMPLE AND VERY ELOQUENT STUDY REPORTED BY [INDISCERNIBLE] AND HIS COLLEAGUES IN 2000, THEY COMPARED WILDTYPE MICE TO AQUAPORIN 4 NULL MICE CREATED BY [INDISCERNIBLE] AND HIS COLLEAGUES AT THE UNIVERSITY OF CINCINNATI. SO THE EXPERIMENT, THE TEST MOUSE COATED WITH STANCH AND IODINE. ANIMALS INJECTED SO [INDISCERNIBLE] TURNS BLUE. YOU SEE ALL THE FUNCTIONAL SWEAT GLANDS. THIS MOUSE HAS SWEAT GLANDS, HYPOFUNCTIONAL. THE MOUSE CAN'T SWEAT. AFTER [INDISCERNIBLE]. NOW, THAT MAY NOT BE OF IMPORTANCE TO MICE LIVING IN CAGES, BUT IT CERTAINLY HAS A LOT OF IMPORTANCE IN TERMS OF HUMAN PHYSIOLOGY. IN SUMMER OF 2003, WESTERN EUROPE EXPERIENCED THE WORST HEAT WAVE IN RECORDED HISTORY. TEMPERATURES OVER 100 DEGREES FAHRENHEIT FOR TWO WEEKS. 15,000 UNEXPECTED DEATHS. INDIVIDUALS IN THEIR 50s, 60S, 70s, WHO WERE DOING ALL RIGHT BY DIDN'T SURVIVE. IT'S OUR BELIEF THAT THE AQUAPORINS THAT ARE PART OF THE EXPLANATION FOR STRESS RESPONSE, AS WE AGE SOME OF THESE PATHWAY WAYS DECLINED. SENSATION OF THIRST MAY BE DIMINISHED. ABILITY TO CONCENTRATE URINE, DIMINISHED. ANY OTHER„i FACTORS SUCH AS INFECTION MIGHT BE ENOUGH TO PUT PEOPLE OVER THE EDGE. PROBABLY WELL A ANTHONY THAT [INDISCERNIBLE]. I'M GOING TO TALK ABOUT THE GLYCEROL HOMLOGS, STRUCTURALLY VERY SIMILAR BUT NOT IDENTICAL. I BORROWED THIS SLIDE FROM [INDISCERNIBLE] AT THE UNIVERSITY OF CALIFORNIA WHERE HE JUXTAPOSED THE POOR LINING RESIDUES IN THE WATER CHANNEL FROM MAMMALIAN RED CELLS, THE DARKER SHADING REPRESENTS THE RESIDUES IN THE WATER CHANNEL. AND THE LIGHTER SHADING REPRESENTS THE CORRESPONDING RESIDUES TIN GLYCEROL TRANSPORTER. YOU CAN SEE THE [INDISCERNIBLE] IS REPLACED BY A HYDRO PHOBIC TRAP DOOR. THIS LARGE [INDISCERNIBLE] PROVIDES THE POSITIVE CHARGE, PARTIAL POSITIVE CHARGE HERE AND HERE TO REPELL PROTONS. THIS IS MISSING IN APOLOGISTERATE TRANSPORTER. A TINY APOLOGIZE SEEN, ALLOWING THIS -- GLYCINE, ALLOWING THIS TRAP DOOR TO OPEN. NOW, I FINISHED MY MEDICAL TRAINING, WAS ON THE FACULTY. NEVER ONCE CONSIDERED THE GLYCEROL TRANSPORT MIGHT HAVE BIOLOGICAL SIGNIFICANCE. IT JUST NEVER DAWNED ON ME. THE PRESENCE OF THE AQUA FOR POOREN -- NOW, ONE SUMMER SEVERAL YEARS AGO I WAS VISITED BY EXECUTIVES FROM THE KRISTIN DEER COMPANY. I DON'T GET A LOT OF VISITORS GOOD THE DIOR COMPANY, EXECUTIVE OFFICE. THEY WANTED TO GIVE ME SOMETHING, BUT GET SOMETHING. THEY WANTED ME TO GIVE A LECTURE IN PARIS. THERE WAS RELEASE OF NEW PRODUCTS, HIDRACTION SKIN CREAM. ALLEGEDLY INCREASED THE SUBTLE INCREASES OF [INDISCERNIBLE] IN SKIN. IF YOU USE ENOUGH YOU'LL LOOK LIKE THIS, WAS NOT PROVEN. [LAUGHTER] TO MY KNOWLEDGE. AND I'M PRETTY SKEPTICAL. AND I SHUT POINT OUT, I HAVE -- I HAVE NO FINAL TIES TO THEM. THEY OFFERED SOME BUT HAD A LOT OF STRINGS ATTACHED. MY WIFE REMINDS ME, MAY NOT HAVE BEEN THE BEST DECISION. THIS YOU HAVE IT. NOW, THOSE WHO READ FRENCH, THIS IS A BACK OF A BEAUT AMAGAZINE. VISIBILITY HYDRATION. SPECTACULAR RESULTS. NOBLE PRIZE IN CHEMISTRY. I SHOWED THIS TO MY MOTHER. 80 YEAR OLD FARM GIRL LIVING ALONE IN MINNESOTA. SHE SMILED, SAID PETER, I THINK YOU'RE FINALLY DOING SOMETHING USEFUL [LAUGHTER] OTHER MOTHERS KNOW US BETTER THAN WE KNEW OURSELVES. BUT I THINK THIS WILL HAVE SOME IMPORTANT APPLICATIONS. I'D PRESENT IN RED CELLS. IT'S PRESENT IN RED CELLS. AND IN RED CELLS PROVIDES AN INTERESTING FUNCTION OF GLYCEROL TRANSPORT, WHICH EVERY MEMBER OF THE TRANSFUSION MEDICINE AUDIENCE RELIESING HOW WE CAN -- SO IT'S FUNCTIONALLY IMPORTANT IN THE TRANSFUSION MEDICINE COMMUNITY. ALSO THE HIGH FREQUENCY GILL ANTIGEN, VERY RARE HIGH FREQUENTLY ANTIGEN. AND THERE ARE SOME RARE INDIVIDUALS WHO ARE AQUAPORIN NULL, THEY HAVE NO RED CELL MANIFESTATIONS. RED CELLS TRANSPORTER IS REDUCED BUT THEY MAY HAVE A DEFECT IN SKIN HYDRATION. SO THERE MAY BE A NEGATIVE PHENOTYPE HERE. NOW, IT TURNS OUT TO BE REALLY IMPORTANT IN MALARIA. BECAUSE MALARIA, AND I'LL TALK ABOUT THIS NOW, IN SOME DEPTH. IT'S AN IMPORTANT CLINICAL DISEASE WHERE THE PARASITE WILL INVADE A RED CELL, A SINGLE PARASITE WILL GROW AND DIVIDE 2, 4, 8, 16, 32, 32 DAUGHTER CELLS WILL GROW RAPIDLY WITHOUT THE INZOOMATIC MACHINERY. IT'S DEPENDENT UPON THE GILL ANTIGEN, THE MEMBRANE GLYCEROL TRANSPORTERS, ALSO PRESENT IN THE VASCULAR MEMBRANE AND PARASITE OWN FOR GLYCEROL UPTAKE. SO AS I SAID HERE IS AN INDIVIDUAL PARASITE. HERE IS 32. THIS CELL WILL BREAK, 32 DAUGHTER CELLINGS ARE RELEASED. YOU CAN DO THE NUMBERS, 23 TIMES 32 IS A THOUSAND. TWO -- HORRENDOUS FEVERS, HIGH LEVELS OF TOXIC MALARIA CRUDE CIRCULATINGS THROUGH THE CIRCULOUS. SO I'LL JUST POINT 2 POINT OF THIS SLIDE. WE'VE KNOCKED THE AQUA GLYCERIN POREN GENE, THE MOUSE VARIANT OF MALARIA. AND WHAT WE FOUND IS THAT THE PARASITE, THE FRACTION OF RED CELLS INFECTED, GOES UP RAPIDLY IN ABOUT A WEEK, TOOK LONGER. THE INFECTION IS DIMINISHED IN VIRULENCE T. MICE SURVIVED LONGER. HERE IS MICE INJECTED WITH THE TILED TYPE, ALL DEAD IN 22 DAYS. SO IT'S INJECTED WITH A MUTANT. WE HAVEN'T CURED THE DISEASE BUT IT SHOWS IT'S IMPORTANT IN TERMS OF THE VIRULENCE. PROBABLY NOT ENOUGH TO TO BE A DRUG TARGET. SO THERE WAS A TIME IN MY CAREER I WANTED TO WORK IN WORLD HEALTH. AND I GOT VERY ACTIVE IN THE LABORATORY BUT I NEVER FORGOT THAT NEED TO GET INVOLVED IN GLOBAL HEALTH ACTIVITIES. BECAME THE DIRECTOR OF THE MALARIA RESEARCH INSTITUTES AT JOHNS HOPKINS. AND HAD THE GREAT FORTUNATE TO BE PART OF OUR PROGRAM AS PART OF THE NIH CENTERS OF EXCELLENCE. THERE ARE TEN CENTERS WORLDWIDE. WE OPERATE THE ONE IN SOUTHERN AFRICA. SO WE'RE WORKING AS YOU CAN SEE IN ZAMBIA. AND ZIMBABWE, THE FORMER -- WE HAVE 3 DIFFERENT SITES. FIELD WORK IS OPENING, GETTING PARASITES, LOOKING FOR DRUG RESISTANCE, INCORRECT CRIED RESISTANT. WHO GETS MALARIA? THE SMALL CHILDREN OF THE DEVELOPING WORLD. CHILDREN LIKE THESE LITTLE BOYS WHO IN PREVIOUS YEARS, PROBABLY ALL HAD MALARIA, NOW CAN BE PROTECTED. AND IT CAN BE TRITED EFFECTIVELY. BUT NOT EVERY ONE IS SO FORTUNATE. HERE IS A LITTLE BOY NEAR DEATH. IN COMA. LIFE WAS SAVED BY A DOCTOR SHOWN ON THE RIGHT HERE, A PEDIATRICIAN DEDICATED HIS WIFE TO WORKING IN SAHARAN AFRICA. THE BOY, WHILE HE ROOFED, HE NEVER REGAINED HIS SITE. HE'S SUSTAINED CEREBRAL MALARIA. SO WE'RE MADE AWARE CONSTANTLY OF THE 600,000 CHILDREN THAT DIED LAST YEAR. THERE IS SEVERAL MILLION WHO ARE LEFT WITH KIDNEY DISEASE, BRAIN DISEASE, SO THE DISEASE EXTENSION IS MUCH LARGER. HERE IS MOUSE SPECIMEN, NORMAL MOUSE -- HERE IS THE BASE OF MEMBRANE, THE CAP LARRY INTERFACE. [INDISCERNIBLE] AQUAPORIN HAVE. HERE IS THE SPECIMEN FROM A MOUSE TREATED WITH MALARIA DEVELOPING CEREBRAL MALARIA, POCKETS OF FLUID THROUGHOUT THE BRAIN. THAT COMBINED WITH INFARCT LEADS TO THE DAMAGE THAT LEFT THIS POOR BOY SIGHTLESS. SO JUST A LITTLE BIT ABOUT OUR INSTITUTE. HERE WE ARE, SURVEILLANCE TEAM. A FEW YEARS BACK. IT'S AMAZING SOMETIMES WHEN WE THINK HOW COMPLEX SOME DISEASES ARE. SIMPLE INTRUSIONS CAN HAVE SOME POWERFUL EFFECTS. MALARIA IS SUCH AN EXAMPLE. EFFECT I'VE -- EFFECTIVE TREATMENT, AGGRESSIVE FOLLOW-UP, THE RATE OF INFECTION DECLINED. THE HOSPITAL ADJACENT TO OUR FIELDIZATION IN EVERY PREVIOUS YEAR HAD 1,000 CHILD AGED 5 AND UNDER ADMITTED, BETWEEN 30 TO 100 SOME DEATHS. PROVIDING EFFECTIVE TREATMENT AND FOLLOWING IT UP WE COULD KNOCK IT DOWN. BUT THERE WAS A MEDICAL STOCK OUTAGE IN 2006, TO THE PARACITES RETURNED RIGHT AWAY, CAME BACK DOWN. THE INTRODUCTS OF INSECURITYICIDE LED DO FURTHER DECLINE IN MALARIA PRESENCE, SO IT'S WAY DOWN. ABOUT 97% BELOW WHAT IT WAS. BY IT'S NOT GONE ENTIRELY. SO WE KNOW WHAT WILL HAPPEN. WE SEIZE OUR EFFORTS THERE -- CREASE OUR EFFORTS THERE, IT WILL COME BACK. THE PROBLEM IS HOW TO TAKE CARE OF MALARIA EVERYWHERE. THAT WILL REQUIRE A LOT OF GEOPOLITICAL WILL. BORDERS DO NOT STOP MALARIA. YOU CAN MAKE PEOPLE CROSS BORDERS WITH PASS PORTED BUT THE MOSKALUKS THAT CARRY THE -- MOSQUITOES THAT CARRY THE MALARIA GO BACK AND FORTH. THE MALARIA MOSQUITO IN AFRICA. AND THEY HAVE THEIR OWN CASCADE OF AQUAPORINS, 8 DIFFERENT AQUAPORINS. SOME ARE WATER SELECTIVE. THESE CAUSE THE MOSQUITOES [TECHNICAL DIFFICULTIES]. HERE WEAN AN RNAi, DIMINISHED FROM THE MOSQUITO. AND TREATED THE MOSQUITOES TO EXPOSURE THROUGH 39 DEGREES. WHICH IS STRESSFUL FOR THEM. THE SURVIVAL TIME IS SHORTENED. LEVELS ARE REDUCED. LIKEWISE, WE LOOKED AT THE NUMBERS OF [INDISCERNIBLE]. WHEN THE MOSQUITO TAKES IN A BLOOD MEAL, THE PARASITE CROSSES THE MID GUT AND FORMED AN OASIS. THE RANGE OF VALUES IS CONSIDERABLE. THE WILDTYPE MOSQUITOES HAD ABOUT TEN, WHEREAS THE PARASITES, REDUCED EXPRESSION HAD ONLY 3. SO SEEMS SOME HOW THIS PRONE IS IMPORTANT FOR THE VILE OF THE MOSQUITO IN STRESS. AND ALSO CONFERS THE ABILITY TO FORM [INDISCERNIBLE]. INTERESTING, BUT HOW CAN WE USE THIS THERAPEUTICALLY? THAT'S A QUESTION I ASK MYSELF ALL THE TIME. I'LL END BY TALKING BRIEFLY ABOUT TWO OTHERS, BACK TO HUMANS, AND MAMMALIAN TISSUES. 7, WHICH IS PRESENT IN FAT. 9, PRESENT IN LIVER. SO DURING FASTING WE FACE A CHALLENGE. WE RUN THROUGH OUR GLYCOGIN LEVELS. HOW DO WE MAINTAIN BLOOD GLUES DOES? ONE OF THE EARLY STEPS, RELEASE OF GLYCEROL FROM FAT. IT'S CLEAR THE WORK OF SEVERAL LABORATORIES THAT 7 ALLOW BLISSERAL RELEASE FROM FAT, TAKEN UP BY THE RIVER THROUGH 9, WHICH IS UPREGULATED DURING FASTING. ALLOWING THE MAINTENANCE OF BLOOD SUGAR, EVEN TO THE LATE STAGES OF STARVATION. THIS IS WORK JEN AT DUKE. NOW, INTERESTING, THEY TURN OUT TO BE PERMEATED BY HEAVY METALS, NOTABLY ARSENIC, UNCHARGED OUGHT NEUTRAL PH. PERMEATED, AND, OF COURSE, ARSENIC IS SOMETHING WE'RE CONCERNED ABOUT. THE GROUND WATER, PUBLIC DRINKING WATT YOU ARE IN THE UNITED STATES IS VERY CLEAN. IN SOME PARTS OF THE WORLD, EASTERN INDIA AND BANGLADESH, THEY PUT IN TUBULES TO TAKE OUT GROUND WATER. IN MOAN LOCATIONS, MANY, THE GROUND WATER IS TOXIC WITH ARSENIC LEVELS, THOUSANDS OF TIMES ABOVE THE ACCEPTABLE LEVEL T WORLD HEALTH ORGANIZATION CALCULATES 140 MILLION INDIVIDUALS IN BANGLADESH, 140 MILLION PEOPLE DRINKING TOXIC WATER EVERY DAY. SO THE ANSWER, OF COURSE, IS PROVISION OF PURE DRINKING WATER. WHAT COULD THIS PROTEIN BE THERE FOR? PROBABLY, THE DETOXIFICATION OF ARSENIC, WHICH ALL MAMMALS FACE DURING EVOLUTION. IN A SIMPLE STUDY COLLABORATION, HERE IS PATO CITE [INDISCERNIBLE] ANTIBODY. HERE IS A KNOCKOUT MOUSE. AND HERE FEATURE S MEASURED -- FECES MEASURED, INJECTED WAS EXCRETED RAPIDLY. NO MICE RETAIN IT AND THEY SUCCUMB READILY. IT'S PROBABLY A DETOXIFYING AGENT FOR ARSENIC AND OTHER HEAVY METALS IN THE DRINKING WATER. PLANTS ALWAYS HAVE AQUAPORIN. THIS SLIDE I BORROWED FROM THE UNIVERSITY OF [INDISCERNIBLE], SHOWS A WILDTYPE AND ENGINEERED TO REDUCE THE EXPRESSION OF ONE OF 35 DIFFERENT FAMILIES OF WATER CHANNELS. IT'S ENOUGH TO SHOW THAT THE PLANT COMPENSATES. IT HAS A NICE [INDISCERNIBLE]. DIMINISHED WATER UP TAKE, MORE THAN ENOUGH TO COMPENSATE. PLANTS COMPETE WITH EACH OTHER DURING DROUGHT. SO IN CLOSING I TALKED ABOUT THE PERMANENTUATION OF THE WATER SELECTIVITY, THE GLYCEROL NITRAIT AND ARSENIC PERMANENTUATIONS. THE STRUCTURAL CATEGORY. AND SOME OF THE DISEASES WHERE THESE ARE NOW ESTABLISHED TO BE INVOLVED. BY THE CHALLENGES IS TO DO SOMETHING USEFUL WITH THIS. THAT'S NOT SO EASY. NOW, OCTOBER IS COMING UP. 3-AND-A-HALF WEEKS A FEW PEOPLE WILL BE WAKENED EARLY IN THE MORNING BY A TELEPHONE CALL. I'LL SHARE MY EXPERIENCE IN OCTOBER, 2003. 5:30 A.M., PHONE RANG. ANSWERED. IT'S A PLEASANT SWEDISH VOICE, THIS IS AN IMPORTANT TELEPHONE CALL. ARE YOU THE PROFESSOR? I SAID I SURE AM. AND CONTINUED TO EXPLAIN I WOULD BE SHARING THE NOBLE BREEZE IN CHEMISTRY WITH RODERICK MCCANNEN. HE IS A MEDICAL DOCTOR WORKING ON CHANNELS AT ROCKEFELLER. THEY'RE GOING ON. INTRODUCED TO MEMBERS OF THE COMMITTEE. I'M THINKING TO MYSELF, DO I TELL THEM THAT I GOT A D IN HIGH SCHOOL CHEMISTRY? [LAUGHTER] DIDN'T SEEM LIKE A GOOD IDEA. THEN I'M STARTING TO IMAGINE MY HIGH SCHOOL CHEMISTRY TEACHER, MR. THORNTON, ASPIRATING CORN FLAKES. I JUST HELD MY PEACE. SAID THANK YOU. AND IN TEN MINUTES THERE WILL BE A PRESS CONFERENCE IN STOCK HOME. YOU BETTER GET READY FOR YOUR DAY. SO I SPRINTED TO THE SHOWER. MY WIFE, MARY, ALWAYS CALM, ALWAYS ORGANIZED CALLED ME MOTHER IN MINNESOTA. TELL HER THE NEWS. MOTHER LISTENS, SOFTLY. SHE SAID MARY, TELL PETER THAT'S VERY NICE. BUT DON'T LET THIS GO TO HIS HEAD. [LAUGHTER] SHE STILL IS ON THAT DO SOMETHING USEFUL BUSINESS, WHICH IS PROPER. TOTALLY PROPER. BUT YOU CAN'T ALWAYS CHOOSE THE LEVEL OF CELEBRATION. DRIVING HOME THAT EVENING -- [LAUGHTER] I NOTICED THE LIQUOR STORE, WAS CELEBRATING THE ANNOUNCEMENT. I'D LIKE TO DEFEND MY REPUTATION. I'M NOT THEIR BEST CUSTOMER BY MY MEASURE. BUT HERE WE ARE IN ON THE STAGE AFTER THE PRIZE. AND I GUESS ANY RESEMBLANCE I HAD WHEN I TOOK OFF THE MUSTACHE. NOW I'VE GROWN A BEARD. I LOOK LIKE SANTA CLAUS. THERE ARE TWO PRIZES, ONE GOES FOR THE ENTIRE WORK OF A FIELD DO INDIVIDUALS. REALLY, THESE REPRESENT THE ADVANCES FROM MANY LABORATORIES. AND IT'S GREAT PR FOR SCIENCE. THE FIRST THING ON PUBLIC RADIO THEY ANNOUNCE. EVEN FOX NEWS WILL TALK ABOUT IT. AMAZING. [LAUGHTER] THE OTHER PRIZE HERE IS MY FAMILY. AND I THINK THAT'S SOMETHING WE ALL HAVE. THE LIVES OF SCIENTISTS ARE NOT EASY, CHALLENGING, BUT THEY CAN BE WE WARDING. WE RELY UPON THEM FOR LOVE AND SUPPORT MAKING ALL THE DIFFERENCE. SO CAREERS OFTEN GO VERY FAST. IT WAS TEN YEARS SINCE YOU WERE IMPORTANT, IT'S 20 YEARS -- BORN. IT'S 20 YEARS. WE THINK ABOUT THE SCIENCE AND LOOK BACK, AND THAT WAS WONDERFUL BUT WE ALSO THINK ABOUT ABOUT THE PEOPLE WE WORKED WITH. THAT WAS REALLY WONDERFUL. THE COLLECTION OF FRIENDS WE'VE HAD FOR OUR ENTIRE CAREERS. THEY COME IN OUR MINDS AND HEARTS. SO THE LAST SLIDE I'D LIKE TO END WITH IS SOMETHING I'VE LEARNED FROM THE YOUNG PEOPLE IN THE LAB. CONNIE LUO, JUST FINISHED. JOINED THE FDA -- FOOD AND DRUG ADMINISTRATION. SHE TAUGHT ME SOMETHING I THOUGHT WAS PRETTY IMPORTANT. THE CHARACTER FOR CRISIS IN CHINESE, IS AT THIS CHARACTERS. WAY, TIME OF DANGER, G, A TIME OF OPPORTUNITY. AND WE THINK OF THE DANGERS OF THE WORLD IN TERMS OF CLIMATE CHANGE, PESTILENCE, DISEASE, AND WE THINK IN TERMS OF SCIENCE. THE ANSWER TO THESE CHALLENGES. I THINK WE ALL HAVE LOTS OF WORK TO DO. SHOULD BE GLAD TO HAVE THE OPPORTUNITY TO DO THAT. WITH THAT, LET ME THANK THE MEMBERS OF THE DEPARTMENT OF TRANSFUSION MEDICINE HERE AT THE NATIONAL INSTITUTES OF HEALTH FOR THE INVITATION TO SPEAK TO YOU. I'LL BE AROUND, THERE IS A RECEPTION AFTER WARD. THANK YOU SO MUCH. [APPLAUSE] >> THANK YOU VERY MUCH FOR THIS GREAT PRESENTATION. AND WE HAVE A COUPLING OF MINUTES FOR -- COUPLE OF MINUTES FOR ANY QUESTIONS THAT YOU MAY HAVE. >> THANK YOU. FANTASTIC TALK. FOR MORE THAN ONE DIMENSION. I HAVE A LOT OF QUESTIONS, BUT BRIEFLY, I WOULD POSE MAYBE 2. ARE THESE AQUAPORINS A SELECTIVE ONE, 1, 2, 3, DEVELOPED MORE DURING THE AGING PROCESS SO THAT THE AGED PEOPLE ARE NOT AS SENSITIVE TO DESTRUCTION OF THE WATER CHANNEL? AND ALSO, ARE THEY A SPECIFIC SITE FOR EACH ONE OF THESE UNITS OF CHANNELS IN THE IMMUNE TISSUE HIKE THE BRAIN YOU MENTIONED, AND ALSO, IMMUNE RESPONSIVE TISSUE? >> WELL, FIRST QUESTION, I BELIEVE THERE PROBABLY IS A DECLINE IN MANY PHYSIOLOGICAL PATHWAYS AS WE AGE. 66, I CAN STILL GO JOGGING. I CAN'T RUN AS FAST AS I USED TO. MY HART WON'T BEAT AS FAST. I CAN'T MOVE OXYGEN AS FAST. I WON'T GET INTO THE VIAGRA BUSINESS. BUT WE BASICALLY COMPENSATE. IN SOME CASES IT MAY BE SIMPLE DECLINE IN THE NUMBER OF TRANSPORT MOLECULES. IT'S NOT CLEARLY ESTABLISHED, THE NUMBER OF AQUAPORINS COUNTED IN TISSUES, REFLECTS AGE. I THINK YOU'RE RIGHT, IT HASN'T BEEN PROVEN. DESECOND QUESTION ABOUT THE SPECIFIC LOCATIONS, I THINK THAT'S WHERE OUR COLLEAGUES, NORWEGIAN COLLEAGUES, DID VERY BEAUTIFUL WORK. AND THE ANSWER IS IT SEEMS THEY'RE VERY, VERY SPECIFICALLY LOCATED. THE AQUAPORIN 2 PROTEIN IS CLEARLY INTRACELLULAR. AND TRAFFIC -- MARK'S TEAM IS WORKING ON THAT RIGHT NOW, DOING VERY CONVINCING WORK. SEEMS TO RARELY, GO TO THE BASAL LATERAL SURFACE, WHEREAS 3 AND 4 MAY BE AT THE BUYSO LATERAL SURFACE. THEY DON'T GET MIXED UP. SEEMS THAT THEY'RE VERY SPECIFIC. AND I THINK THAT'S HELD TRUE IF ALL THE SPECIES HAVE BEEN EXAMINED THAT I'M AWARE OF. DID I ANSWER YOUR QUESTION. >> YES. COULD BE ALSO THEY ARE MORE SENSITIVE, IF THEY ARE PRIVILEGED TISSUE TOWARD OXIDATION. AS YOU -- >> SURE. >> THAT SOUND LIKE CHEMISTRY, NOT MY FIELD. [LAUGHTER] MY APOLOGIES. >> THANK YOU. >> THANK YOU. YES, PLEASE. >> YOU MENTIONED SEVERAL VARIETIES OF PROTEINS. -- AQUAPORINS. IS THE TRANSPORT RATE DIFFERENT IN ALL THESE DIFFERENT TYPES OF AQUAPORINS? >> THE ACTUAL WATER TRANSPORT RATE IS NOT EASY TO MEASURE PRECISELY. SO THE ESTIMATES MUST HAVE PLUS OR MINUS 25% MEASURING ERROR. BUT IT APPEARS THAT THE AQUAPORINS, THE WATER SELECTED ONES, ARE ALL FAIRLY SIMILAR. THERE IS SOME PAPERS SUPPORTING THAT ONE MIGHT BE MORE THAN ANOTHER, BY THEY'RE OFTEN CONFLICTING RESULTS. GLYCEROL TRANSPORTING HOMOLOGUES HAVE WATER PERMEABILITY, APPEARS TO BE LESS THAN THE AQUAPORIN. BUT THEY'RE ALSO PERMEATED BY GLYCEROL, OR UREA, OTHER SMALL UNCHARGED -- INCLUDING ARSON. THIS ARE DIFFERENCES IN THE CLASSES, I DO NOT FEEL CONFIDENT THAT AQUAPORIN 2 HAS A GREATER UNIT CAPACITY THAN AQUAPORIN 1. THEY'RE BOTH VERY LARGE. I MEAN CALCULATE THE NUMBER OF THESE CHANNELS, THIS HAS BEEN DONE. I THINK ONE OF MARK'S EARLY STUDIES. THE NUMBER OF CHANNELS IN THE KNOWN WATER TRANSPORT CONVOLUTED TUBULES, IT'S NEGATIVE TO EXPLAIN THE MASSIVE -- ENOUGH TO EXPLAIN THE MASSIVE WATER UNIT. >> GLYCERIN IS MUCH BIGGER THAN WATCHER. SO IS THERE SOME FLEXIBILITY IN THIS? >> SURE. >> IN THE CHANNEL? TO LARGER STRUCTURE? >> YES. PROBABLY WENT OVER TOO QUICKLY, THERE WAS A SLIDE THAT I BORROWED THAT -- AT THE LAWRENCE BERKELEY LABORATORY. THE AQUAPORIN, 3 IN DIAMETER. THE AVERAGE IS 2.8 AN STROMS. THE GLYCEROL TRANSPORTER IS MISSING A KEY HISTOGENE, AND THE PHENOMENAL ALANIN, THIS HAS BEEN DONE BY MOLECULAR DYNAMIC STIMULATION, ILLINOIS -- GROUP MILL [INDISCERNIBLE]. THE IT DROPS LIKE A DROP DOOR ENLARGING THE PORETIOUS SO WE CAN EXPLAIN AND UNDERSTAND IT. YOU WOULD THINK ANYTHING LARGE ENOUGH WOULD LET WATER GO THROUGH INDISCRIMINATELY. INCREASED LEVEL. THAT IS NOT FOUND. SO ONE QUESTION I'M OFTEN ASKED, THERE GATING? ARE THESE OPEN AND SHUT PERMANENTLY? OR FLICKERING? AND THERE WITH ONE MEMBER OF THE FAMILY I DIDN'T TALK ABOUT. AQUAPORIN 6. TURNS OUT TO HAVE AN ION CONDUCTIVITY. AND IT SEEMS TO BE GATED BY PH. AND IT'S RAPIDLY FLICKERING. SO IT MAY BE THERE IS A GATING THAT WE CAN'T MEASURE IN TERMS OF WATER BECAUSE IT'S ELECTRICALLY SILENT. THAT'S ABOUT ALL I KNOW ABOUT IT. >> ALSO SHOWS THE [INDISCERNIBLE]. THE ALCOHOL GOES TO THIS CHANNEL. >> FLORIDA WAS A PHONE TO THE MEASURE THE -- THERE WAS AN EFFORT TO MEASURE THE ALCOHOL, EXPLAINING NEURO EFFECTS OF ALCOHOL BUT IT'S QUITE HYDRO PHOBIC. AND THE BARRIER TO DEFASHION IS MINIMAL. SO IT HAS VERY, VERY HIGH LEVEL OF PERMANENTUATION JUST TO THE SIMPLE MEMBRANES ITSELF. SO I GUESS WE CAN'T EXPLAIN THAT. >> THANK YOU FOR THE TALK. >> THANK YOU SO MUCH. >> THE QUESTION OF [INDISCERNIBLE]. VARIANTS OF PROTEIN INCLUDING COLTEN BLOODTEN RELATIVE TO COMMON? DO YOU SEE A SCIENTIFIC REASON OR INTEREST IN CHARACTERIZATION OF PROTEIN VARIANCE, PROTON VARIANCE IN THE POPULATION? LIKE WHERE ARE THE PROTEINS GOING TO? HOW WOULD THAT BE REGULATED? >> SURE. IT'S SOMETHING WE'VE NOT ADDRESSED. I THINK IDENTIFYING MOL ARMORPHISMS SOMETIMES CAN BE REVEALING. OFTEN TIMES, YOU GET RESULTS THAT YOU CAN'T INITIALLY EXPLAIN IN THAT LEAD YOU IN A NEW DIRECTION. THERE MAY BE SOME FUNCTIONAL DIFFERENCE IN THESE POLYMORPHISMS THAT WE DON'T KNOW ABOUT. SO I WOULD HOPE SOMEONE WOULD PURSUE THAT. TOO LATE IN ANY CAREER TO DO THAT. BUT I THINK HERE IN THIS GROUP, MUST BE SOME INTEREST IN MOLECULAR GENETICS, EVEN THE [INDISCERNIBLE]. I DO LIKE THE NAME COLVIN WETTER WETTER -- BETTER THAN COLTEN. >> [INAUDIBLE] >> WE HAVE TO GET THE FUNDING. >> IF THERE IS NO ADDITIONAL QUESTIONS, THEN THERE IS A RECEPTION NEXT STORE IN THE NATIONAL LIBRARY OF MEDICINE. AND WE'LL MEET THERE. THANK YOU VERY MUCH FOR THIS -- [APPLAUSE]